Induction of prolonged infiltration of T lymphocytes and transient T lymphocyte-dependent collagen deposition in mouse lungs following adenoviral gene transfer of CCL18
Induction of prolonged infiltration of T lymphocytes and transient T lymphocyte-dependent collagen deposition in mouse lungs following adenoviral gene transfer of CCL18
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DOI：
10.1002/art.21950
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发表时间：
2006-08-01
影响因子：
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通讯作者：
Atamas, Sergei P.
中科院分区：
文献类型：
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作者：
Luzina, Irina G.;Papadimitriou, John C.;Atamas, Sergei P.
Objective. CCL 18水平在硬皮病肺病和其他与T淋巴细胞参与相关的纤维化肺病患者中升高。我们试图确定单独的CCL 18是否可以诱导小鼠肺中的肺T淋巴细胞浸润和纤维化。构建腺病毒载体并用于将CCL 18体内递送至小鼠肺。免疫组化、流式细胞术和酶联免疫吸附试验分析用于评估所产生的变化。CCL 18的过度表达导致大量T淋巴细胞在血管周围和支气管周围浸润。尽管CCL 18的表达在感染后第7天达到峰值，但浸润持续至感染后第64天。浸润细胞增殖细胞核抗原和TUNEL阴性，表明细胞运输的作用，而不是增殖和凋亡，在浸润动力学。还观察到肺泡结构的斑片状破坏和与浸润相关的胶原积聚。这些变化是浸润依赖性的，而不是CCL 18依赖性的，因为用抗淋巴细胞血清治疗完全消除了CCL 18诱导的变化。浸润几乎完全由最低限度活化的T淋巴细胞组成，CD 69表达增加最小，CD 25、Fas、FasL或CD 40 L表达无变化。尽管局部存在与浸润和扭曲肺泡结构相关的活性TGF β 1，但促纤维化细胞因子转化生长因子β 1（TGF β 1）或白细胞介素-13的总肺水平没有增加。CCL 18预刺激体外培养的原代T淋巴细胞可诱导T淋巴细胞/成纤维细胞共培养物中TGF β 1和胶原合成的上调。CCL 18通过TGF β 1依赖性机制促进T淋巴细胞的选择性长期肺浸润和胶原蛋白的浸润依赖性积累。
Objective. Levels of CCL18 are elevated in patients with scleroderma lung disease and other fibrotic pulmonary diseases associated with T lymphocyte involvement. We sought to determine whether CCL18 alone can induce pulmonary T lymphocytic infiltration and fibrosis in mouse lungs.Methods. An adenovirus vector was constructed and used for CCL18 delivery to mouse lungs in vivo. Immunohistochemical, flow cytometric, and enzyme-linked immunosorbent assay analyses were used to assess the resulting changes.Results. Overexpression of CCL18 led to massive perivascular and peribronchial infiltration of T lymphocytes. Although the expression of CCL18 peaked on day 7, the infiltration persisted up to day 64 after infection. The infiltrates were negative for proliferating cell nuclear antigen and TUNEL, suggesting the role of cell trafficking, rather than proliferation and apoptosis, in the infiltration dynamics. Patchy destruction of the alveolar architecture and collagen accumulation in association with the infiltrates were also noticed. These changes were infiltration-dependent, rather than CCL18-dependent, since treatment with antilymphocyte serum completely abrogated the CCL18-induced changes. The infiltrates consisted almost exclusively of T lymphocytes that were minimally activated, with a minimal increase in the expression of CD69 and no changes in the expression of CD25, Fas, FasL, or CD40L. There was no increase in total pulmonary levels of profibrotic cytokines transforming growth factor beta 1 (TGF beta 1) or interleukin-13, although active TGF beta 1 was present locally in association with the infiltrates and areas of distorted alveolar architecture. Prestimulation of primary T lymphocytes with CCL18 in vitro caused an up-regulation of TGF beta 1 and collagen production in T lymphocyte/fibroblast cocultures.Conclusion. CCL18 promotes selective, long-term pulmonary infiltration of T lymphocytes and infiltration-dependent accumulation of collagen through a TGF beta 1-dependent mechanism.